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Schizophrenia (SZ) is a biochemically complex disorder characterized by widespread defects in multiple metabolic pathways whose dynamic interactions, until recently, have been difficult to examine. Rather, evidence for these alterations has been collected piecemeal, limiting the potential to inform our understanding of the interactions amongst relevant biochemical pathways. We herein review perturbations in purine and neurotransmitter metabolism observed in early SZ using a metabolomic approach. Purine catabolism is an underappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. We have observed a homeostatic imbalance of purine catabolism in first-episode neuroleptic-naive patients with SZ (FENNS). Precursor and product relationships within purine pathways are tightly correlated. Although some of these correlations persist across disease or medication status, others appear to be lost among FENNS suggesting that steady formation of the antioxidant uric acid via purine catabolism is altered early in the course of illness. As is the case for within-pathway correlations, there are also significant cross-pathway correlations between respective purine and tryptophan pathway metabolites. By contrast, purine metabolites show significant cross-pathway correlation only with tyrosine, and not with its metabolites. Furthermore, several purine metabolites (uric acid, guanosine, or xanthine) are each significantly correlated with 5-hydroxyindoleacetic acid (5-HIAA) in healthy controls, but not in FENNS at baseline or 4-week after antipsychotic treatment. Taken together, the above findings suggest that purine catabolism strongly associates with the tryptophan pathways leading to serotonin (5-HT) and kynurenine metabolites. The Lack of a significant correlation between purine metabolites and 5-HIAA, suggests alterations in key 5-HT pathways that may both be modified by and contribute to oxidative stress via purine catabolism in FENNS.

The present study examined serum levels of adenosine deaminase (ADA), an adenosine metabolizing enzyme, in neuroleptic-naive patients with recent-onset schizophrenia and age-matched healthy comparison subjects. ADA levels were found to be higher among patients, and revealed a possible link between evening rise and severity of auditory hallucinations as well as morning rise and severity of avolition-apathy in patients with schizophrenia. These findings suggest the potential utility of serum ADA as a peripheral biomarker of schizophrenia. [ABSTRACT FROM AUTHOR]

Schizophrenia (SZ) is a biochemically complex disorder characterized by widespread defects in multiple metabolic pathways whose dynamic interactions, until recently, have been difficult to examine. Rather, evidence for these alterations has been collected piecemeal, limiting the potential to inform our understanding of the interactions amongst relevant biochemical pathways. We herein review perturbations in purine and neurotransmitter metabolism observed in early SZ using a metabolomic approach. Purine catabolism is an underappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. We have observed a homeostatic imbalance of purine catabolism in first-episode neuroleptic-naïve patients with SZ (FENNS). Precursor and product relationships within purine pathways are tightly correlated. Although some of these correlations persist across disease or medication status, others appear to be lost among FENNS suggesting that steady formation of the antioxidant uric acid (UA) via purine catabolism is altered early in the course of illness. As is the case for within-pathway correlations, there are also significant cross-pathway correlations between respective purine and tryptophan (TRP) pathway metabolites. By contrast, purine metabolites show significant cross-pathway correlation only with tyrosine, and not with its metabolites. Furthermore, several purine metabolites (UA, guanosine, or xanthine) are each significantly correlated with 5-hydroxyindoleacetic acid (5-HIAA) in healthy controls, but not in FENNS at baseline or 4-week after antipsychotic treatment. Taken together, the above findings suggest that purine catabolism strongly associates with the TRP pathways leading to serotonin (5-hydroxytryptamine, 5-HT) and kynurenine metabolites. The lack of a significant correlation between purine metabolites and 5-HIAA, suggests alterations in key 5-HT pathways that may both be modified by and contribute to oxidative stress via purine catabolism in FENNS. [ABSTRACT FROM AUTHOR]

One branch of the tryptophan catabolic cascade is the kynurenine pathway, which produces neurotoxic [3-hydroxykynurenine (3-OHKY), quinolinic acid] and neuroinhibitory (kynurenic acid) compounds. Kynurenic acid acts as a competitive antagonist at the glycine site of N-methyl-d-asparate receptors at high concentrations and as a non-competitive antagonist on the α7-nicotinic acetylcholine receptor at low concentrations. Kynurenine compounds also influence cognitive functions known to be disrupted in schizophrenia. Alterations in tryptophan metabolism are therefore of potential significance for the pathophysiology of this disorder. In this paper, tryptophan metabolites were measured from plasma using high-pressure liquid chromatography coupled with electrochemical coulometric array detection, and relationships were tested between these metabolic signatures and clinical symptoms for 25 first-episode neuroleptic-naive schizophrenia patients. Blood samples were collected and clinical and neurological symptoms were rated at baseline and again at 4 wk following initiation of treatment. Level of 3-OHKY and total clinical symptom scores were correlated when patients were unmedicated and neuroleptic-naive, and this relationship differed significantly from the correlation observed for patients 4 wk after beginning treatment. Baseline psychosis symptoms were predicted only by neurological symptoms. Moreover, baseline 3-OHKY predicted clinical change at 4 wk, with the lowest concentrations of 3-OHKY being associated with the greatest improvement in symptoms. Taken together, our findings suggest a neurotoxic product of tryptophan metabolism, 3-OHKY, predicts severity of clinical symptoms during the early phase of illness and before exposure to antipsychotic drugs. Baseline level of 3-OHKY may also predict the degree of clinical improvement following brief treatment with antipsychotics. [ABSTRACT FROM PUBLISHER]

Abstract: Introduction: While several studies have shown an association of QEEG band power with negative symptoms in patients with schizophrenia, this has not yet been investigated in a sample with neuroleptic-naïve first-episode patients (NNFE) up to now. From literature we hypothesized delta (0.5–4Hz) and theta (4–8Hz) power to be augmented and alpha (8–12Hz) power to be decreased with increased negative symptoms in NNFE. Materials and methods: The sample consisted of 27 NNFE. Psychopathology was rated with the Scale for the Assessment of Negative Symptoms (SANS). EEG was recorded from 21 electrodes according to the 10/20 system. Spectral analysis was performed on mean power of 8 electrodes in seven frequency bands after artefact removal. Linear regressions were calculated with log transformed power as dependent and psychopathology as independent variable. We controlled for medication, drugs, age, sex, education and day time of EEG recording. Results: A positive correlation of SANS global score with power in delta and theta frequency bands could be confirmed in NNFE. In the alpha1 (8–10Hz) band we found no significant correlation with negative symptoms and in the alpha2 (10–12Hz) band there was a positive correlation with SANS (p =0.069). Beta1 (12–15Hz) power also correlated positively with SANS. Discussion: The present results confirm the correlation of negative symptoms with power of slow frequency bands. In addition to previous studies in chronic schizophrenia patients, the effect was shown in NNFE, which is compatible with augmented slow wave power being a marker for negative symptoms in psychosis. [Copyright &y& Elsevier]

Abstract: The study of corpus callosal morphometry is important to unravel the underlying connectivity disturbance in schizophrenia. We studied the corpus callosal area in schizophrenia subjects compared to healthy subjects, while controlling for several confounders that could affect morphometric measures of the corpus callosum (CC). Areas of the whole CC and its sub-regions obtained by two geometric partitioning schemes were studied in 23 right-handed neuroleptic-naïve, recent-onset, schizophrenia patients and compared with 23 right-handed age-, sex- and education-matched healthy subjects. The patients did not differ from controls in whole CC area. On tripartite division of the CC, the area of the anterior sub-region was significantly higher in patients compared to controls. On radial division into 5 sub-regions, the anterior truncus area was significantly higher in patients compared to controls. There was a significant effect of gender (F>M) on the area measures; however there was no significant diagnosis ⁎ gender effect. Age, age of onset, duration of illness and psychopathology ratings did not show any significant correlations with whole CC area and area of CC sub-regions. The finding of increased area of the anterior truncus that possibly comprises white fibres connecting the temporal association cortices could be indicative of an “abnormal functional hyperconnection” involving these regions in positive symptom schizophrenia. Additionally, the finding of females having larger areas of the whole CC and of the anterior and middle sub-regions could reflect a “normal hyperconnection” underlying increased ambilaterality in females. [Copyright &y& Elsevier]

Drug induced parkinsonism (DIP) is directly related to dopamine D2 receptor blockade. However, there are many references describing parkinsonian signs (PS) in naive-patients. In our previous study, we observed lower DAT binding in a group of first-episode schizophrenic patients after short-term treatment with risperidone, compared with age-matched healthy controls. To clarify if DAT decrease could be an illness trait, excluding the effect of antipsychotics on DAT availability, and to determine whether DAT availability before treatment with antipsychotics may predict subsequent development of PS. A new series of 20 neuroleptic-naive schizophrenic patients and 15 healthy subjects was recruited. SPECT with [123I] FP-CIT (DaTSCAN®) was performed before starting antipsychotics and after 4 weeks of treatment. PS and psychopathological status were assessed by the Simpson–Angus (SAS), CGI and PANSS scales. Quantitative analyses of SPECTs were performed using ROIs placed in the caudate, putamen and occipital cortex. Schizophrenic patients showed lower DAT binding compared with the healthy subjects at baseline ( p<0.001) and after a 4-week-treatment period ( p=0.001). Six out of eight schizophrenic patients of the DIP group were symptomatic for PS at baseline, in comparison to two out of 12 in the NoDIP group. Nonetheless, no differences were observed on DAT between DIP and NoDIP, neither at baseline ( p=0.360) nor at endpoint ( p=0.984). Finally, no differences between baseline–endpoint DAT binding were observed, neither in the DIP group ( p=0.767) nor in the NoDIP group ( p=0.093). Our new series of first-episode naive-schizophrenic patients (1) points out DAT dysfunction as an illness trait due to the significantly lower DAT binding in schizophrenic patients in comparison to healthy subjects; (2) supports the results of other authors who describe PS in never-treated patients; (3) confirms that [123I] FP-CIT does not allow us to predict which patients will develop parkinsonism due to the lack of differences between DIP and NoDIP patients; and (4) confirms a null effect of antipsychotics on DAT due to the lack of differences in [123I] FP-CIT before and after a 4-week-treatment period. [ABSTRACT FROM AUTHOR]

Recent findings suggest that free radical-mediated pathological processes may underlie membrane deficits that have been observed in schizophrenia. We have previously demonstrated that both total antioxidant status (TAS) and individual antioxidants were significantly reduced in plasma of chronic schizophrenic patients, on and off haloperidol. To test whether reductions in plasma antioxidants are independent of treatment or illness progression, levels of plasma antioxidants were evaluated in 43 patients at first-episode of psychosis, 31 patients meeting DSM-IV criteria for schizophrenia or schizoaffective disorder (reconfirmed after 6 months) and 12 patients with primary mood (bipolar or depressive (BP/D)) disorder, at neuroleptic-naive baseline as well as 40 age- and sex-matched normal controls (NC). The major plasma antioxidants albumin, uric acid and bilirubin were all significantly lower in the first-episode schizophrenic, but not in the BP/D patients, than in normal controls. Factors that can affect these antioxidants—age, gender, diet and smoking—were examined. Body mass index (BMI) was significantly lower in patients, but was not correlated with plasma albumin and bilirubin; there was a trend for a correlation with uric acid in schizophrenic patients. Lower antioxidant levels were independent of smoking status of patients. The present data suggest that a defect in the antioxidant defense system (AODS), which may lead to oxidative damage, occurs early in the course of illness and is independent of treatment effects. [Copyright &y& Elsevier]